National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bengaluru, India.
Department of Computational Biology, University of Lausanne (UNIL), Switzerland.
Mol Oncol. 2024 May;18(5):1189-1208. doi: 10.1002/1878-0261.13559. Epub 2023 Dec 9.
Human papillomavirus (HPV) infections are the primary drivers of cervical cancers, and often HPV DNA gets integrated into the host genome. Although the oncogenic impact of HPV encoded genes is relatively well known, the cis-regulatory effect of integrated HPV DNA on host chromatin structure and gene regulation remains less understood. We investigated genome-wide patterns of HPV integrations and associated host gene expression changes in the context of host chromatin states and topologically associating domains (TADs). HPV integrations were significantly enriched in active chromatin regions and depleted in inactive ones. Interestingly, regardless of chromatin state, genomic regions flanking HPV integrations showed transcriptional upregulation. Nevertheless, upregulation (both local and long-range) was mostly confined to TADs with integration, but not affecting adjacent TADs. Few TADs showed recurrent integrations associated with overexpression of oncogenes within them (e.g. MYC, PVT1, TP63 and ERBB2) regardless of proximity. Hi-C and 4C-seq analyses in cervical cancer cell line (HeLa) demonstrated chromatin looping interactions between integrated HPV and MYC/PVT1 regions (~ 500 kb apart), leading to allele-specific overexpression. Based on these, we propose HPV integrations can trigger multimodal oncogenic activation to promote cancer progression.
人乳头瘤病毒（HPV）感染是宫颈癌的主要驱动因素，HPV DNA 通常会整合到宿主基因组中。虽然 HPV 编码基因的致癌作用相对较为明确，但整合 HPV DNA 对宿主染色质结构和基因调控的顺式调控作用仍知之甚少。我们研究了 HPV 整合与宿主染色质状态和拓扑关联域（TAD）相关的宿主基因表达变化的全基因组模式。HPV 整合在活性染色质区域中显著富集，而在非活性染色质区域中则明显减少。有趣的是，无论染色质状态如何，HPV 整合侧翼的基因组区域都表现出转录上调。然而，上调（局部和长程）主要局限于具有整合的 TAD 内，但不会影响相邻的 TAD。少数 TAD 表现出与其中过表达癌基因相关的反复整合（例如 MYC、PVT1、TP63 和 ERBB2），无论其位置如何。Hi-C 和 4C-seq 分析在宫颈癌细胞系（HeLa）中表明，整合的 HPV 和 MYC/PVT1 区域之间存在染色质环互作（相隔约 500kb），导致等位基因特异性过表达。基于这些发现，我们提出 HPV 整合可以触发多模式致癌激活，促进癌症进展。
